It has been ten years since the completion of the human genome project, but we are still far from understanding the mechanisms through which gene activities are regulated. It has been increasingly recognized that epigenetic mechanisms play an important role in cell-type specific gene regulation, and disruption of epigenetic regulation has been implicated in many diseases. However, our current knowledge has been limited to one-dimensional epigenetic patterns, whereas the three-dimensional chromatin structure remains poorly characterized. While it has been long recognized that chromatin interactions may play a critical role in long- range gene regulation, global investigations have been hampered by the technical difficulty to map genome-wide chromatin interactions at a high resolution. In this proposal, we will develop novel computational methods to systematically characterize the chromatin states from histone modification data, and to predict chromatin interactions from these states. We will leverage the large amount of histone modification data that are available in the public domain, and further validate our computational methods in the laboratories. Our proposed research will provide a much needed tool that can enable a guided approach to genome-wide interrogations of chromatin interactions, thereby greatly reducing the experimental cost to generate much needed data. Ultimately, the insights generated from these investigations will help elucidating the molecular pathways for a wide variety of diseases. PUBLIC HEALTH RELEVANCE: The proposed research will develop computational methods to prediction long-range chromatin interactions by leveraging the large amount of histone modification data generated by ENCODE and Roadmap Epigenomics Project. Our work will significantly facilitate genome-scale investigation of long-range gene regulatory mechanisms, which will in turn generate new insights into disease pathways and lead to new therapeutic approaches.